title: Mapping the interactions between the Alzheimer's Aβ-peptide and human serum albumin beyond domain resolution.
abstract: Human serum albumin (HSA) is a potent inhibitor of Aβ self-association and this novel, to our knowledge, function of HSA is of potential therapeutic interest for the treatment of Alzheimer's disease. It is known that HSA interacts with Aβ oligomers through binding sites evenly partitioned across the three albumin domains and with comparable affinities. However, as of this writing, no information is available on the HSA-Aβ interactions beyond domain resolution. Here, we map the HSA-Aβ interactions at subdomain and peptide resolution. We show that each separate subdomain of HSA domain 3 inhibits Aβ self-association. We also show that fatty acids (FAs) compete with Aβ oligomers for binding to domain 3, but the determinant of the HSA/Aβ oligomer interactions are markedly distinct from those of FAs. Although salt bridges with the FA carboxylate determine the FA binding affinities, hydrophobic contacts are pivotal for Aβ oligomer recognition. Specifically, we identified a site of Aβ oligomer recognition that spans the HSA (494-515) region and aligns with the central hydrophobic core of Aβ. The HSA (495-515) segment includes residues affected by FA binding and this segment is prone to self-associate into β-amyloids, suggesting that sites involved in fibrilization may provide a lead to develop inhibitors of Aβ self-association.
authors.affiliation: Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Moustafa
authors.initials: M
authors.lastname: Algamal
authors.forename: Julijana
authors.initials: J
authors.lastname: Milojevic
authors.forename: Naeimeh
authors.initials: N
authors.lastname: Jafari
authors.forename: William
authors.initials: W
authors.lastname: Zhang
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Melacini
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012709:Serum Albumin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D005227:Fatty Acids; D010446:Peptide Fragments; D012709:Serum Albumin; C075222:amyloid beta-protein (1-42)
keywords: AD; Alzheimer’s Disease; BBB; Blood Brain Barrier; CNS; CSF; Central Nervous System; Cerebrospinal Fluid; FA; Fatty Acid; HSA; Human Serum Albumin; ICP; Inductively Coupled Plasma; MA; Myristic Acid; RC; Random Coil; SL; STD; STR; Saturation Transfer Difference; Saturation Transfer Reference; Spin-Lock; WG; Watergate water-suppression NMR technique